A subset of the 65 different papillomaviruses (HPVs) that have been identified is associated with urogenital cancers in humans. Although most cervical carcinomas have integrated HPV such as HPV-16 and HPV-18, the specific role of HPVs in the pathogenesis of the disease is unclear because only a small proportion of the women positive for HPV develop cancer. Thus, the exact role of HPVs in the multistage carcinogenesis process requires further study. There is no question that HPVs found in cancers can immortalize cells in vitro, induce aberrant differentiation and chromosomal alterations; but malignancy cannot be demonstrated with immunodeficient mice. Treatment of HPV-immortalized cells with known chemical carcinogens or tobacco smoke condensates caused toxicity, chromosome rearrangements and amplification of HPV-16 or -18, suggesting that they have a role in cervical cancer, but tumors were not produced. Herpes simplex virus-2 (HSV-2) is also sexually transmitted and has been often considered a cofactor for cervical cancer. HSV-2 failed to immortalize control epithelial cells, but when a subfragment was transfected into HPV immortalized cells, it was retained; and in some cases the combination produced carcinomas in nude mice. Recent epidemiologic evidence suggests that HIV-positive women have higher recurrence and death rates of cervical cancer than HIV-negative women. Because evidence exists correlating antibody titers to human herpesvirus-6 (HHV-6) and progression of HIV infection, it was hypothesized that HHV-6 may also have a direct effect on expression of HPVs associated with cervical cancer. The current studies demonstrate that HHV-6 can infect HPV containing cells and increase HPV expression. HHV-6 may have a direct effect on initiation or progression of carcinomas of the uterine cervix. The fact that HIV and HPVs share some pathways in their natural histories suggests that their combination may be associated with progression to cervical carcinoma.